Indanone Potentiators of Metabotropic Glutamate Receptors

Abstract

The present invention is directed to compounds which are potentiators of metabotropic glutamate receptors, including the mGluR2 receptor, and which are useful in the treatment or prevention of neurological and psychiatric disorders associated with glutamate dysfunction and diseases in which metabotropic glutamate receptors are involved. The invention is also directed to pharmaceutical compositions comprising these compounds and the use of these compounds and compositions in the prevention or treatment of such diseases in which metabotropic glutamate receptors are involved.

1 - 27 . (canceled) 
     
     
         28 . A compound of the formula I: 
       
         
           
           
               
               
           
         
         wherein: 
         A is phenyl or pyridyl; 
         W is selected from the group consisting of:
 (1) tetrazolyl, 
 (2) CO 2 H, 
 (3) NHSO 2 C 1-16 alkyl, 
 (4) NHSO 2 -phenyl, wherein the phenyl is unsubstituted or substituted with C 1-6 alkyl, and 
 (5) CONHCO—C 1-6 alkyl; 
 
         X is selected from the group consisting of:
 (1) —O—, 
 (2) —S—, and 
 (3) a bond; 
 (4) —O-phenyl-, 
 (5) —S-phenyl-, and 
 (6) -phenyl-; 
 
         Y is selected from the group consisting of:
 (1) —O—, 
 (2) —NH(CO)—, and 
 (3) a bond; 
 
         R 1a  and R 1b  are independently selected from the group consisting of:
 (1) hydrogen, 
 (2) C 1-6 alkyl, which is unsubstituted or substituted with a substituent selected from:
 (a) halogen, 
 (b) hydroxyl, and 
 (c) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents independently selected from halogen, cyano, CF 3 , hydroxyl, C 1-16 alkyl, and OC 1-6 alkyl, 
 
 (3) C 3-7 cycloalkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl, and 
 (4) phenyl, wherein the phenyl is unsubstituted or substituted with 1-5 substituents independently selected from halogen, hydroxyl, cyano, CF 3 , C 1-16 alkyl, and OC 1-16 alkyl, wherein the C 1-6 alkyl and OC 1-6 alkyl are linear or branched and optionally substituted with 1-5 halogen; 
 
         R 2  is selected from the group consisting of:
 (1) halogen, 
 (2) hydroxyl, 
 (3) OC 1-6 alkyl, and 
 (4) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl; 
 
         R 3  is selected from the group consisting of:
 (1) halogen, and 
 (2) C 1-6 alkyl, which is unsubstituted or substituted with halogen, hydroxyl or phenyl; 
 
         R 4  may include multiple substituents and is independently selected from the group consisting of:
 (1) hydrogen, 
 (2) halogen, 
 (3) C 1-6 alkyl, and 
 (4) —O—C 1-6 alkyl, 
 or R 4  may be joined to the phenyl ring at an adjacent carbon to form a dihydrofuranyl ring; 
 
         m is an integer selected from 0, 1, 2 and 3; 
         n is an integer selected from 0, 1, 2, 3, 4, 5 and 6; 
         and pharmaceutically acceptable salts thereof. 
       
     
     
         29 . The compound of  claim 28  wherein A is phenyl. 
     
     
         30 . The compound of  claim 28  wherein A is pyridyl. 
     
     
         31 . The compound of  claim 28  wherein W is CO 2 H. 
     
     
         32 . The compound of  claim 28  wherein X is a bond and Y is —O—. 
     
     
         33 . The compound of  claim 28  wherein X is —O-phenyl-. 
     
     
         34 . The compound of  claim 34  wherein X is -phenyl-. 
     
     
         35 . The compound of  claim 28  wherein R 1a  is C 1-6 alkyl. 
     
     
         36 . The compound of  claim 28  wherein R 1a  is C 5-6 cycloalkyl. 
     
     
         37 . The compound of  claim 28  wherein R 1a  is phenyl. 
     
     
         38 . The compound of  claim 28  wherein R 1b  is hydrogen. 
     
     
         39 . The compound of  claim 28  wherein R 1b  is C 1-6 alkyl. 
     
     
         40 . The compound of  claim 28  wherein R 2  is chloro and R 3  is chloro. 
     
     
         41 . The compound of  claim 28  wherein R 4  is hydrogen or bromo. 
     
     
         42 . The compound of  claim 28  wherein m is 0. 
     
     
         43 . The compound of  claim 28  wherein n is 1. 
     
     
         44 . The compound of  claim 28  wherein n is 2. 
     
     
         45 . A compound which is selected from the group consisting of: 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-{3-[4-(2H-tetrazol-5-yl)-phenoxy]-propoxy}-indan-1-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-{2-[4-(2H-tetrazol-5-yl)-phenoxy]-ethoxy}-indan-1-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-[4-(2H-tetrazol-5-yl)-benzyloxy]-indan-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-[5-(2H-tetrazol-5-yl)-pentyloxy]-indan-n-one; 
       6,7-Dichloro-2-cyclopentyl-5-[4-(2H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       6,7-Dichloro-2-propyl-5-[4-(2H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-[4-(2H-tetrazol-5-yl)-butoxy]-indan-1-one; 
       6,7-Dichloro-2-isopropyl-5-[4-(2H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-[4-(2H-tetrazol-5-yl)-phenylethynyl]-indan-1-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-{2-[4-(2H-tetrazol-5-yl)-phenyl]-ethyl}-indan-1-one; 
       6,7-Dichloro-2,2-dimethyl-5-[4-(2H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       2-(6,7-Dichloro-2-cyclopentyl-2-methyl-1-oxo-indan-5-yloxy)-N-[4-(1H-tetrazol-5-yl)-phenyl]-acetamide; 
       6,7-Dichloro-2-cyclopentylmethyl-2-methyl-5-[4-(1H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-[3-(1H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-[3-(1H-tetrazol-5-yl)-propoxy]-indan-1-one; 
       4-(6,7-Dichloro-2-cyclopentyl-2-methyl-1-oxo-indan-5-yloxymethyl)-benzoic acid; 
       6,7-Dichloro-2-methyl-2-phenyl-5-[4-(1H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       2-Butyl-6,7-dichloro-2-cyclopentyl-5-[4-(1H-tetrazol-5-yl)-benzyloxy]-indan-1-one; 
       N-[4-(6,7-Dichloro-2-cyclopentyl-2-methyl-1-oxo-indan-5-yloxymethyl)-benzoyl]-methanesulfonamide; 
       N-[4-(6,7-Dichloro-2-cyclopentyl-2-methyl-1-oxo-indan-5-yloxymethyl)-benzoyl]-4-methyl-benzenesulfonamide; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-[4-(1H-tetrazol-5-yl)-phenyl]-indan-1-one; 
       3,5-dibromo-4-{[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-N-(methylsulfonyl)benzamide; 
       N-acetyl-4-{[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}benzamide; 
       6,7-dichloro-2-cyclopentyl-2-methyl-5-{[5-(1H-tetrazol-5-yl)pyridin-2-yl]methoxy}indan-1-one; 
       6,7-dichloro-2-cyclopentyl-2-methyl-5-{4-[4-(2H-tetrazol-5-yl)phenoxy]butoxy} indan-1-one; 
       6,7-dichloro-2-cyclopentyl-2-methyl-5-{4-[3-(2H-tetrazol-5-yl)phenoxy]butoxy} indan-1-one; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       5-(3-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}phenyl)nicotinic acid; 
       2-Cyclopentyl-6,7-dimethyl-5-({3-[5-(1H-tetrazol-5-yl)pyridin-3-yl]benzyl}oxy)indan-1-one; 
       6,7-dichloro-2-cyclopentyl-2-methyl-5-({3-[4-(2H-tetrazol-5-yl)phenoxy]benzyl}oxy)indan-1-one 
       6-chloro-2-cyclopentyl-2-methyl-5-({3-[4-(2H-tetrazol-5-yl)phenoxy]benzyl}oxy)indan-1-one; 
       2-cyclopentyl-6,7-dimethyl-5-{[3′-(2H-tetrazol-5-yl)biphenyl-3-yl]methoxy}indan-1-one; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-{[(6,7-Dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       3′-{[(2-cyclopentyl-2,6,7-trimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-{[(2-cyclopentyl-2,6,7-trimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       2-cyclopentyl-6,7-dimethyl-5-{[4′-(2H-tetrazol-5-yl)biphenyl-3-yl]methoxy}indan-1-one; 
       3-(4-{4-[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]butoxy}phenyl)propanoic acid; 
       3′-{[(6,7-Dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       5-(3-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}phenyl)pyridine-2-carboxylic acid; 
       4-(3-{[(2-cyclopentyl-2,6,7-trimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}phenoxy)benzoic acid; 
       3′-{[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-N-(methylsulfonyl)biphenyl-3-carboxamide; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-2-methylbiphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-3-methylbiphenyl-4-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-2-methylbiphenyl-4-carboxylic acid; 
       4-Chloro-3′-{[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-6-methylbiphenyl-3-carboxylic acid; 
       3′-{[(6,7-Dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-{[(6,7-Dichloro-2-isopropyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-{[(6,7-Dichloro-1-oxo-2-propyl-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       5-({2-chloro-5-[4-(2H-tetrazol-5-yl)phenoxy]benzyl}oxy)-2-cyclopentyl-6,7-dimethylindan-1-one; 
       4-(3-{[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}phenoxy)benzoic acid; 
       4-(3-{[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}phenoxy)benzoic acid; 
       3′-{[(6,7-Dichloro-2,2-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-{[(6,7-Dichloro-2-methyl-1-oxo-2-phenyl-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-{[(2-Butyl-6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-({[6,7-Dichloro-2-(cyclopentylmethyl)-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl]oxy}methyl)biphenyl-4-carboxylic acid; 
       3′-{[(7-Chloro-2-cyclopentyl-6-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-6-fluorobiphenyl-3-carboxylic acid 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-2-fluorobiphenyl-4-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-6-methoxybiphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-2,6-dimethoxybiphenyl-4-carboxylic acid; 
       3-Chloro-3′-{[(2-cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-4-carboxylic acid; 
       4-Chloro-3′-{[(6,7-dichloro-2-cyclopentyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       4-Chloro-3′-{[(6,7-dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-5-fluorobiphenyl-3-carboxylic acid; 
       3′-{[(6,7-Dichloro-2-cyclopentyl-2-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-5-fluorobiphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-4-hydroxybiphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-4-methoxybiphenyl-3-carboxylic acid; 
       5-(3-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}phenyl)-2,3-dihydro-1-benzofuran-7-carboxylic acid; 
       3′-{[(7-Chloro-2-cyclopentyl-6-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       3′-{[(7-Chloro-2-cyclopentyl-6-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-5-fluorobiphenyl-3-carboxylic acid; 
       4-Chloro-3′-{[(7-chloro-2-cyclopentyl-6-methyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}-4-fluorobiphenyl-3-carboxylic acid; 
       3′-{[(2-Cyclopentyl-6,7-dimethyl-1-oxo-2,3-dihydro-1H-inden-5-yl)oxy]methyl}biphenyl-3,4-dicarboxylic acid; 
       6,7-Dichloro-2-cyclopentyl-2-methyl-5-{[3′-(2H-tetrazol-5-yl)biphenyl-3-yl]methoxy}indan-1-one; 
       or a pharmaceutically acceptable salt thereof. 
     
     
         46 . A pharmaceutical composition which comprises an inert carrier and a compound of  claim 28  or a pharmaceutically acceptable salt thereof. 
     
     
         47 . A method for potentiation of metabotorpic glutamate receptor activity in a mammal which comprises the administration of an effective amount of the compound of  claim 28  or a pharmaceutically acceptable salt thereof. 
     
     
         48 . A method for treating, controlling, ameliorating or reducing the risk of a neurological and psychiatric disorders associated with glutamate dysfunction in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of a compound of  claim 28  or a pharmaceutically acceptable salt thereof. 
     
     
         49 . A method for treating, controlling, ameliorating or reducing the risk of anxiety in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of a compound of  claim 28  or a pharmaceutically acceptable salt thereof. 
     
     
         50 . A method for treating, controlling, ameliorating or reducing the risk of depression in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of a compound of  claim 28  or a pharmaceutically acceptable salt thereof. 
     
     
         51 . A method for treating, controlling, ameliorating or reducing the risk of schizophrenia in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of a compound of  claim 28  or a pharmaceutically acceptable salt thereof. 
     
     
         52 . A method for treating, controlling, ameliorating or reducing the risk of epilepsy in a mammalian patient in need of such which comprises administering to the patient a therapeutically effective amount of a compound of  claim 28  or a pharmaceutically acceptable salt thereof.